Researchers discover genetic variation that hinders weight loss in obese adolescents

Study conducted in Brazil detected polymorphism in leptin receptor gene that modifies energy balance and neuroendocrine regulation.

By Maria Fernanda Ziegler  |  Agência FAPESP – A gene alteration that hinders the process of weight loss has been identified in research conducted at Escola Paulista de Medicina (EPM), the medical school of the Federal University of São Paulo (UNIFESP) in Brazil.

The study, which involved 76 obese adolescents between the ages of 15 and 19 years, shows that a polymorphism in the leptin receptor gene simultaneously modifies neuroendocrine regulation and energy balance. Leptin is a hormone that notifies the brain when a person has eaten enough, and their calorie intake is sufficient.

The adolescents, who weighed between 101 kg and 120 kg, took part for a year in a weight loss program that included exercise training, clinical surveillance, and psychological and nutritional therapy administered by a multidisciplinary team of physicians, dietitians, psychologists, physical educators and physiotherapists. Half of the adolescents lost an average of 10% of their initial weight, while the other half lost 6%.

“The difference intrigued us. It’s not that the other half failed to get results. They reduced visceral fat, and their biochemical tests improved. Nevertheless, it couldn’t have been just a matter of more or less effort or motivation. So we decided to take a look at the genetics,” said Flávia Corgosinho, lead author of the study published in the journal Neuropeptides.

The article resulted from Corgosinho’s PhD research, supported by a scholarship from the Ministry of Education’s Office for Faculty Development (CAPES), and a research project supported by FAPESP for which the principal investigator was Ana Raimunda Dâmaso, a professor at UNIFESP.

The genetic investigation showed that the volunteers who responded less well to the program had an altered leptin gene receptor (LEPR rs2767485).

The researchers analyzed the effects of this polymorphism in a single gene among more than 500 obesity-related genes. According to Corgosinho, the genetic variation in question is recessive, and at least one allele was altered in half of the volunteers, a significant sample of obese adolescents in São Paulo City.

“We didn’t have a control group, so we can’t extrapolate the findings to the general population,” Corgosinho told Agência FAPESP.

Studying adolescents is important, she added, especially considering the increasing difficulty of losing weight as one gets older. “In early childhood and adolescence, the metabolism accelerates because these are growth phases,” Dâmaso explained. “They offer a great opportunity to lose weight and change unhealthy habits. Otherwise, the probability that an obese adolescent will become an obese adult is estimated at 80%.”

More hunger

The researchers also discovered that volunteers with the genetic variant that hindered weight loss had higher levels of hunger neuropeptides – central nervous system efferent signals regulating appetite – than those without the genetic variant.

“Levels of hunger-signaling molecules such as NPY, AgRP, and melanin-concentrating hormone (MCH) were far higher in the volunteers with the genetic alteration,” Corgosinho said. “That means that theoretically, they should feel hungrier.”

Clinical follow-up showed that the weight loss therapy enabled the adolescents to reduce these neuropeptides to levels similar to those found in participants without the genetic variant. Based on blood work, the researchers detected a tendency to regularize these hunger signaling molecules, but one of them (AgRP) continued to rise.

“So it’s clear that the group started therapy with high levels of hunger-signaling molecules. They did improve during the program, but it remained hard to regulate these neuropeptides that activate hunger, and it’s no accident that weight loss was more complicated for these individuals,” Corgosinho said.

Excessive levels of leptin

Leptin is a hormone produced and secreted mainly by adipose tissue. One of its functions is to participate in neuroendocrine control of the organism’s energy balance. Although its production is directly associated with adipose mass, it acts in the brain region called the hypothalamus by stimulating the neurons and neuropeptides linked to satiety.

Previous research by the group showed that high levels of leptin (hyperleptinemia) in obese adolescents were not effective in that they did not significantly inhibit hunger or increase energy expenditure.

According to Corgosinho, there are several possible explanations. “Excess leptin may damage the receptor or overactivate negative feedback. The fact is that the reason for this response hasn’t been clearly established,” she said.

Theoretically speaking, higher levels of leptin should mean increased satiety and fat oxidation, but the opposite appears to occur in obesity, with excessive leptin making the receptor inefficient and potentially resistant to the action of this hormone, which may fail to cross the blood brain-barrier.

“We found hyperleptinemia in both groups of obese adolescents in our study, as expected. However, leptin levels returned to normal after weight loss only in the group without the polymorphism,” Dâmaso told Agência FAPESP.

Weight loss should correlate with lower levels of leptin and normal regulation of the neuroendocrine system mediated by this hormone, bolstering both satiety and energy expenditure. “When this mechanism is active, there’s less likelihood of weight rebounds or yo-yo effects, and appetite control improves,” Dâmaso said.

According to the researchers, other findings of the study that have to do with lipid metabolism and the inflammatory process – insulin, insulin resistance, and cholesterol – are being prepared for publication.

“We’re looking for strategies to optimize the weight loss process,” Corgosinho said. “We’ve identified the difficulty, and now we must propose solutions. This population may need a functional food to get the same benefits or physical exercise with different intensity than that used in the program to achieve the same results.”

The Neuropeptides article “LEPR polymorphism may affect energy balance during weight loss among Brazilian obese adolescents” (doi: 10.1016/j.npep.2017.07.007) by Flávia Campos Corgosinho, Sandro Soares Almeida, Lian Tock, João Bosco Pesquero, Ronaldo Carvalho Araújo, Ana Paula Grotti Clemente, Bárbara Dal'Molin Netto, Raquel Munhoz da Silveira Campos, Deborah Cristina Landi Masquio, Joana Pereira de Carvalho Ferreira, Priscila de Lima Sanches, Aline de Piano Ganen, Marcelo Macedo Rogero, Lila Missae Oyama, Sergio Tufik, Marco Túlio de Mello and Ana Raimunda Dâmaso can be retrieved from: sciencedirect.com/science/article/pii/S014341791730029X?via%3Dihub.